Abstract Introduction/Objective Drug overdose related deaths in the US have shown a four-fold increase over the past two decades, increasing from 6.1 to 21.7 per 100,000, the increasing majority of which involve synthetic opioid use. With this continuing increase, it is important for pathologists to become aware of unusual gross and microscopic changes related to unconventional modes of drug abuse. A less recognized unconventional method for opiate abusers to ingest these substances exemplified by our two cases is by crushing oral tablets and inhaling or injecting the drug intravenously, subcutaneously or intramuscularly. Methods The two cases being presented show morphological features of acute and chronic opiate abuse by autopsy study. Case 1 was a 38-year old female, who underwent spinal fusion surgery 1 month prior, and was found unresponsive at home. Case 2 was a 37-year-old female with a history of Antiphospholipid Antibody Syndrome (APA) and upper limb DVTs who was found unresponsive one day after elective utero-vaginal prolapse surgery. Results At autopsy, Case 1 showed extensive embolization of polarizable foreign body material (possible “pill filler”) and fibrin in small and medium sized vessels without inflammatory reaction in the lungs bilaterally. The foreign material was also present in the small vessels of the heart associated with multifocal acute inflammation, hemorrhage, foreign body giant cell reaction and multiple myocardial infarcts (elevated troponin levels clinically). Blood and vitreous fluid were positive for oxycodone. At autopsy, Case 2 showed an extensive angiocentric miliary pattern of granulomatous reaction to polarizable foreign material, consistent with pill filler in the lungs bilaterally. This foreign material was also present within the lumens and walls of pulmonary vessels and in the skin of the legs. Chronic changes of hypertrophic cardiomyopathy, hepatic cirrhosis and congestive splenomegaly were evident. The blood oxycodone levels were ten times the normal limit. Conclusion These cases illustrate the importance of recognizing the clinical and morphological features of unorthodox acute and chronic opiate abuse. Lack of familiarity with their differing features can lead to a delay in diagnosis and institution of appropriate timely management and treatment.